Biologically active 17 alpha-ethynyl-16,17-dihydroxy-13-alkylgon-4-en-3-ones

ABSTRACT

13 -ALKYLGONA - 16A-HYDROXY-3-METHOXYGONA-1-3,5(10)TRIEN-17-ONE IS CONVERTED TO ITS 16A-TETRAHYDROPYRANYLOXY DERIVATIVE WHICH IS IN TURN REDUCED TO THE CORRESPONDING 17B-OL. THIS COMPOUND IS CONVERTED BY BIRCH REDUCTION TO THE CORRESPONDING 2,5(10)-DIENE WHICH IN TURN IS OXIDIZED TO THE 17-KETONE. TREATMENT OF THE 17-KETONE WITH ETHYNYL GRIGNARD FOLLOWED BY ACID HYDROLYSIS AFFORDS THE 16A-HYDROXY TITLE COMPOUND. TREATMENT OF THE 17-KETONE WITH LITHIUM ACETYLIDE-ETHYLENE DIAMINE COMPLEX AFFORDS THE 16B-HYDROXY TITLE COMPOUND. THE TITLE COMPOUNDS HAVE PROGESTATIONAL ACTIVITY.

United States Patent U.S. Cl. 260-23955 4 Claims ABSTRACT OF THE DISCLOSURE 13 alkylgona l6rx-hydroxy-3-methoXyg0na-1,3,5(10)- trien-17-one is converted to its 16a-tetrahydropyranyloxy derivative which is in turn reduced to the corresponding 175-01. This compound is converted by Birch reduction to the corresponding 2,5 ()-diene which in turn is oxidized to the l7-ketone. Treatment of the 17-ketone with ethynyl Grignard followed by acid hydrolysis affords the l6a-hydroxy title compound. Treatment of the 17-ketone with lithium acetylide-ethylene diamine complex affords the 16B-hydroxy title compound. The title compounds have progestational activity.

DESCRIPTION OF THE INVENTION The invention sought to be patented in a first composi tion aspect resides in the concept of a compound of the structure wherein R is alkyl of from 1 to 4 carbon atoms. The symbol MN indicates that the configuration at carbon atom 16 is either a or [3; both are included in the invention.

The tangible embodiments of the first composition aspect of the invention possess the inherent applied use characteristic of exerting progestational effects upon administration to warm-blooded animals.

The invention sought to be patented in a second composition aspect resides in the concept of a compound of the structure R f \l/ J M 0 i N wherein R is alkyl of from 1 to 4 carbon atoms, R is alkyl of from 1 to 8 carbon atoms, and X is 0:0 or

The tangible embodiments of the second composition aspect of the invention possess the inherent applied use characteristic of being intermediates in the preparation of the compounds of the first composition aspect of the invention.

The invention sought to be patented in its process aspect resides in the concept of a process for the preparation of a 13-alkyl-16,6,17fi-dihydroxy-l7a-ethynylgon-4-en-3- 3,763,149 Patented Oct. 2, 1973 ice one compound which comprises treating a compound of the structure wherein R is alkyl of from 1 to 4 carbon atoms, R is alkyl of from 1 to 8 carbon atoms, and Y is a protected hydroxyl group, with lithium acetylide-ethylene diamine complex in dimethylsulfoxide/benzene, followed by acid hydrolysis.

In the following description of the process aspect of the invention and the preparation of the composition aspects of the invention, reference will be made, for convenience, to a particular embodiment thereof wherein R is ethyl. It is to be understood, however, that this discussion is equally applicable to all embodiments of the invention.

Referring to the following flow chart, where the compounds are assigned Roman numerals for ease of identification, the starting material, 13-ethyl-16u-hydroxy-3- methoxygona-1,3,5(l0)-trien-17-one (I) may be prepared by means known to those skilled in the art (British Pat. 1,115,954). Reaction of I with dihydropyran, for example in the presence of ethanol, pyridine, and acetyl chloride, in benzene affords 13-ethyl-3-methoxy-la-(tetrahydropyran-2-yloxy)-gona 1,3,5 (10) trien-l7-one (II), which upon reduction of the 17-carbonyl function, for example with lithium aluminum tri-tert. butoxyhydride in tetrahydrofuran or with sodium borohydride in methanol, yields 13 ethyl 3 methoxy-l6a-(tetrahydropyran-Z-yloxy)- gona-1,3,5(10)-trien-17fl-ol (III). Reduction of III under Birch conditions with lithium metal and liquid ammonia affords 13 ethyl 3 methoxy 16oz (tetrahydropyran- 2-yloxy)gona-2,5(10)-dien-17;9-0l (IV), which, upon oxidation with dimethylsulfoxide and acetic anhydride affords the corresponding l7-0ne compound (V). Treatment of V with ethynyl Grignard such as ethynyl magnesium bromide in a solvent such as tetrahydrofuran followed by hydrolysis with aqueous mineral acid, such as aqueous hydrochloric acid in a miscible solvent such as methanol affords the product 16a,17 8-dihydroxy-13-ethyl-17u-ethynylgon-4-en-3-one (VI). Treatment of V with lithium acetylide-ethylene diamine complex in dimethylsulfoxide/ben- 50 zene affords the epimeric product 16,8,1713-dihydroxy-l3- ethyl-17a-ethynylgon-4-en-3-one (VII).

E; I -O MeO OH Et --O MeO III

. on m M60 l H I 1' MeO OH OH m '--ozon El |--CECH VII vr While the discussion of reaction step V to VII involved a reactant containing a tetrahydropyranyloxy substituent at position 16, it is to be understood that this aspect of the invention is not so limited. Any of the various groups known as protecting groups for an hydroxyl function may be used instead of tetrahydropyranyloxy, so long as they are stable under the basic conditions of the reaction and are readily removable thereafter.

In employing the compounds of the first composition aspect of the invention to produce a progestational elfect, the compounds may be administered by either oral or parenteral routes. The amount of compound to be administered will vary depending on the route of administration, the particular compound employed, the particular animal involved, and the degree of response desired. Ideally, the dosage should be individualized in each case. Generally, a dose of 1 mg./kg. body weight will be sufficient to nroduce the desired progestational eifect.

The following examples further illustrate the best mode contemplated by the inventor of carrying his invention:

EXAMPLE 1 dl-I3 ethyI-3-methoXygona-I,3,5(10)-trien-16u,17,8-diol,

l6-formate Cool dimethylformamide (60 ml.) with a methanol-ice bath, drip in methanesulfonyl chloride (10 ml.) with stirring followed by dl-13-ethyl-2-methoxygona-1,3,5 (10)- triene-16a,17fl-diol (3.00 g.). Stir, remove the cold bath and continue stirring at room temperature for 1 hour.

Pour the reaction into a solution of pyridine (35 ml.) in ice-water. Stir for 1 hour then extract with ethyl acetateether. Wash, dry and evaporate the extract in vacuo. Dissolve the residue in methylene chloride, treat with activated charcoal, filter and evaporate the methylene chloride in vacuo. Cover the oil with heptane, warm and dilute with benzene. Let stand to crystallize. Filter to obtain 2.59 g., M.P. 146-148". Purify a sample (0.58 g.) by retreatment with charcoal as above and crystallize from isopropanol to get 0.43 g. of the pure title product, M.P. 153-155.

2.85 to 3.0 and 5.8411.

Analysis (percent): C, 73.28; H, 8.23. Calcd. for 0211 12 04 (percent): C, 73.22; H, 8.19.

EXAMPLE 2 dl-l3-ethyl-3-methoxy-l6a-hydroxygona- 1,3,5 10) -trien- 17-one, formate Dissolve dl 13-ethyl-3-methoxygona-1,3,5(10)-triene- 16a,17/5'-diol, 16-formate (2.00 g.) in acetone (50 ml.), stir then drip in 8 N chromic acid solution (total 3 ml.) over 0.5 hour. Stir 10 minutes more than add isopropanol (30 ml.) followed by water (250 ml.). Extract the mixture with ethyl acetate then Wash, dry and evaporate the extract in vacuo. Treat the resulting oil in methylene chloride with activated charcoal, filter and evaporate in vacuo. Crystallize the oil from isopropanol to get 1.56 g. of the pure title product, M.P. 125128.

A 5.72 and 5.81u

muX

Analysis (percent): C, 73.84; H, 7.96. Calcd. for C H O (percent): C, 73.66; H, 7.66.

EXAMPLE 3 dl-13 -ethyl-3-methoxy- 1 6e-hydroxygona- 1 ,3,5 (10)-trien- 17-one Cool a solution of sodium hydroxide (0.80 g.) in methanol (60 ml.) to about 5 C., then add dl-l3-ethyl- 3 methoxy 16oz hydroxygona-l,3,5(10)-trien-17-one, formate (2.00 g.). Stir the cold reaction for 45 minutes then quench by adding cold saturated ammonium chloride solution (200 ml.) dropwise. Filter and dry the resulting precipitate then dissolve it in methylene chloride and treat with activated charcoal. Filter, evaporate the solvent in vacuo and dissolve the oil in hot isopropanol. Let cool and stand to crystallize. Filter to obtain 1.26 g. of the pure title product, M.P. 158461".

a 2.96 and 5.78u

max.

Analysis (percent): C, 76.62; H, 8.71. Calcd. for C H O (percent): C, 76.40; H, 8.34.

EXAMPLE 4 dI-13-ethyl-3-methoxy-16a-(tetrahydropyran-Z-yloxy) gona-1,3,5(10)-trien-17-0ne solvent in vacuo and crystallize the resulting oil from methanol to obtain 7.52 g. of pure title product, M.P. 104l06,

KB max EXAMPLE 5 dl-13-ethyl-3-methoxy-16a-(tetrahydropyran-Z-yloxy) gona-1,3,5()-trien-1713-01 Cool tetrahydrofuran (50 ml.) with a methanol-ice bath, add lithium aluminum tritertbutoxy hydride (1.5 g.) then add dl-l3-ethyl-3-methoxy-16a-(tetrahydropyran- 2-yloxy)gona-1,3,5(10)-trien-17-one (1.00 g.) and continue stirring, allowing to warm to room temperature, for 18 hours. Add water (5 ml.) stir, then follow with more water (200 ml.) added dropwise with stirring. Extract with ether then Wash, dry and evaporate the extract in vacuo. Crystallize the resulting gum from ether-hexane to get 0.69 g. of the title product, M.P. 130-139".

EXAMPLE 6 dl-l3-ethyl-3-methoxy-16a-(tetrahydropyran-Z-yloxy) gona-l,3,5( 10 -trien17fl-ol Stir a mixture of dl-13-ethyl-3-methoxy-16ot-(tetrahydropyran 2 yloxy)gona-1,3,5(10)-trien-17-one (2.00 g.) and methanol (50 ml.) with cooling then add sodium borohydride (1.00 g.). Stir the cooled reaction for 3 hours, then at room temperature add a further 1.00 g. of sodium borohydride, with stirring, in small portions over a period of 2 hours. Continue stirring at room temperature overnight. Add water (200 m1.) then filter the resulting precipitate onto filter-aid. Dry the mixture, extract with tetrahydrofuran, filter and evaporate the solvent in vacuo. Crystallize the oil from ether-hexane to get 1.66 g. of title product, M.P. 132-138.

max.

Analysis (percent): C, 75.12; H, 9.22. Calcd. for C H O (percent): C, 74.96; H, 9.06.

EXAMPLE 7 dl-l3-ethyl-3-methoxygona-1,3,5(10)-triene-16a,17,8-diol Dissolve dl-l3-ethyl-3-methoxy-l6u-(tetrahydropyran- 2-yloxy)gona-1,3,5(10)trien- 17B 01 (500 mg.) in methanol (20 ml.), stir then add conc. hydrochloric acid (10 drops). Stir at room temperature for 1 hour then add water (150 ml.) dropwise, stir 0.5 hour then filter the precipitate onto filter-aid. Dry the mixture, extract with tetrahydrot'uran, filter and evaporate the extract in vacuo. Treat the residue in tetrahydrofuran with activated charcoal, filter and evaporate in vacuo. crystallize from absolute ethanol to get 210 mg. of the title product, M.P. 189-191 EXAMPLE 8 dl-13-ethyl-3-methoxy-16u-(tetrahydropyran-Z-yloxy) gona-2,5( 10 -dien- 175-01 Dissolve dl-13-ethyl 3 methoxy 16a (tetrahydropyran-2-yloxy) gone-1,3,5 (10) trien 17 8 01 (3.0 g.) in dry tetrahydrofuran (80 ml.), add l-methoxy-Z-propanol (50 ml.) and distilled liquid ammonia (300 ml.), stir at the temperature of liquid ammonia then add lithium metal (5.0 g.) in small pieces at a rate to prevent vigorous refluxing of the ammonia (Dry-Ice acetone condenser) over a period of 3 hours. Stir for an additional 1 hour then add enough absolute ethanol to quench the blue color. Add solid ammonium chloride (30 g.) then hot water to drive-off the ammonia. Filter the precipitate onto filteraid, dry and extract the mixture with tetrahydrofuran. Evaporate the solvent in vacuo then dissolve the oil in ether-tetrahydrofuran and a little pyridine, treat with activated charcoal, filter and evaporate in vacuo. Crystallize from hexane to get 1.85 g. of the title product, M.P. 150- 156.

A533,: 3.0, 5.88 and 5.99 1

Evaporate the mother liquors in vacuo and crystallize the oil from methanol to get a further 0.45 g. of the title max.

2.98, 5.90 and 6.02;;

Analysis (percent): C, 74.35; H, 9.54. Calcd. for C H O (percent): C,74.59; H, 9.52.

EXAMPLE 9 a'l- 1 3-ethyl-3-methoxy- 1 6a- (tetrahydropyran-Z- yloxy)gona-2,5(10)-dien-17-one Suspend dl- 1 3-ethyl-3-methoxy- 1 6w (tetrahydropyran- 2-yloxy)gona2,5(l0)-dien-17fi-ol (1.50 g.) in DMSO (25 ml.) and acetic anhydride (6 ml.) and let stand with occasional swirling for 2 hours. Rinse the side of the flask with 5 ml. more of DMSO and let the reaction stand at room temperature for 22 hours. Pour the reaction into icesaturated sodium bicarbonate solution. Filter and dry the resulting precipitate then dissolve the solid in ether containing a little pyridine, treat with activated charcoal, filter and evaporate the solvent in vacuo. Crystallize the oil from methanol to get 0.89 g. of the pure title product, M.P. 124-128".

A 2.95 to 3.10, 5.75, 5.90 and 600a Analysis (percent): C, 74.85; H, 8.95. Calcd. for c25H 3O4 (percent): C, H, 9.06.

EXAMPLE. 10

dl-13-ethyl-17a-ethynyl-16,13,17fi-dihydroxygon- 4-en-3-one Dissolve dl-13-ethyl-3-methoxy-16a-(tetrahydropyran- 2-yloxy)gona 2,5(10)dien-17-one in dry benzene (40 ml.), dilute with dry DMSO ml.) then bubble purified acetylene through the stirring solution for 1.5 hours. Add lithium acetylide-ethylene diamine complex (3.5 g.) stir for 2 hours then add another 3.5 g. of the reagent complex and continue stirring for 1 hour. Pour the reaction into ice water, extract with ethyl acetate-ether. Then wash, dry and evaporate the extract in vacuo. Treat the residue in tetrahydrofuran with activated charcoal, filter and remove the solvent in vacuo. Cover the residue with methanol (50 ml.) add a solution of methanol (200 ml.)-conc. hydrochloric acid 30 ml.) and water (30 ml.). Gently warm the mixture on the steam bath for 5 minutes then stir at room temperature for 1 hour. Warm the reaction again for 5 minutes, stir 0.5 hour at room temperature then add water (500 ml.). Add solid sodium chloride (100 g.) and extract with ether-ethyl acetate. Wash, dry and evaporate the extract in vacuo. Dissolve the resulting oil in ether, treat with activated charcoal quickly, filter and evaporate the ether in vacuo. Crystallize the resulting oil by scratching in ether to obtain 2.20 g. of title product, M.P. 171-173". Further purify the solid by treatment with charcoal as above in tetrahydrofuran followed by crystallization from ether to get 1.80 g. of the pure title product, M.P. 175-177".

REE; 2.95 to 3.07, 6.02 and 6.21 1. 35.13. 238.5 mp. (6 17,100)

Analysis (percent): C, 76.93; H, 8.98. Calcd. for C H O (percent): C, 76.79; H, 8.59.

EXAMPLE 1 1 dl-13-ethyl-17a-ethnyl-16u,17;3-dihydroxygon- 4-en-3-one Equip a flask with magnetic stirrer, condenser and gasmlet tube, charge with dry tetrahydrofuran (250 ml.) and 3 M ethereal methyl magnesium bromide (100 ml.) then bubble purified acetylene through the stirred solution for 2.5 hours. Add dl-13-ethyl-3-methoxy 16oz (tetrahydropyran-Z-yloxy)gona-2,5(10)-clien 17 one (3.60 g.) then gently reflux with stirring under acetylene for 3 hours. Cool and allow the reaction to stand overnight. Pour into 20% ammonium chloride solution, extract with etherethyl acetate then wash, dry and evaporate the extract in vacuo. Treat the resulting gum in tetrahydrofuran with activated charcoal, filter and evaporate in vacuo. Cover the gum with methanol (50 ml.) then add a previously prepared solution of methanol (100 ml.) conc. hydrochloric acid (20 ml.) and water (20 ml.). Stir for 1 hour then gently warm on the steam bath for minutes. Cool, stir at room temperature 1 hour more then add water (500 ml.). Filter the precipitate onto filter-aid dry and extract with tetrahydrofuran. Filter and evaporate the solvent in vacuo, then crystallize the title product from ether to get 90 mg., M.P. 177-180".

EXAMPLE 12 dl-l3-ethyl-16a,17fl-dihydroxygon-4-en-3-one Add a solution of d!-13-ethyl-3-methoxygona-1,3,5(10)- triene16u,17;8-di0l (2.00 g.) in tetrahydrofuran (100 ml.) to freshly distilled liquid ammonia (250 ml.), stir then add lithium metal (3.0 g.) in small portions over 1 hour (a Dry-Ice acetone condenser is used to maintain the temperature for liquid ammonia). Stir a further 1 hour, then add absolute ethanol dropwise to quench the blue color. Add Water (200 ml.) then filter and dry the resulting precipitate of dl-l3-ethyl-3-methoxygona-2,5( 10) -diene-l6u, 17B-diol. To the crude solid add a solution of methanol (100 ml.), Water (10 ml.) and cone. hydrochloric acid (10 ml.) and reflux for 2.5 hours. Cool and pour the reaction into saturated brine then extract with ether. Wash dry and evaporate the extract in vacuo. Triturate the solid with ether, filter and dry to get 715 mg. of the product, M.P. 1 87-188". Further purify a sample (300 mg.) by dissolving it in warm methylene chloride, passing the solution through a bed of anhydrous magnesium sulfate and replacing the solvent with benzene by boiling on the steam-bath. Let the solution stand (add a little ether) then filter to get 230 mg. of title product, M.P. 1 83l 84.

A 3.02, 6.02 and 6.22 1

max.

Analysis (percent): C, 74.81; H, 9.41. Calcd. for C19H2803 (percent): C, H, 9.27.

EXAMPLE 13 dl-13-ethyl-l6a,17fi-dihydroxygon-4-en-3-one, 16-formate KB A max 3.02, 5.86 and 6.07

EXAMPLE 14 dl-l3-ethyl-16et-hydroxygon-4-ene-3,17-dione, formate Cool dimethylformamide (50 ml.) with an ice-methanol bath, stir and add methanesulfonyl chloride (15 ml.) dropwise followed by dl-l3-ethyl-16a,175dihydroxygon- 4-en-3-one (3.00 g.). Stir cold for 5 minutes then at room temperature for 45 minutes. Pour the reaction into a solution of pyridine (40 ml.) and ice-water, stir for 1 hour then extract with ethyl-ethyl acetate. Wash, dry and evaporate the extract in vacuo. Treat the oil in methylene chloride-ether with activated charcoal, filter and evaporate the solvent in vacuo to get dl-13-ethyl-16a,17B-dihydroxygon-4-en-3-one, 16-formate as an oil which is best oxidized without further isolation. Dissolve this oil in acetone (60 ml.), add anhydrous sodium sulfate (5 g.), stir and cool with an ice-bath. Add 8 N chromic acid so lution (3 ml.) dropwise with stirring over 1.5 hours, remove the ice bath and stir at room temperature for 5 minutes then quench by adding isopropanol (10 ml.) and water (250 ml.). Extract with ethyl acetate then wash dry and evaporate the extract in vacuo. Dissolve the residue in methylene chloride, treat with activated charcoal, filter and evaporate in vacuo, then crystallize from benzene to get 1.74 g. of pure title product, M.P. 180-183".

A 5.70, 5.82, 6.03 and 6.19 A523? 239 my. (6 15,860)

Analysis (percent): C, 72.74; H, 8.16. Calcd. for C H O (percent): C, 72.70; H, 7.93.

EXAMPLE l5 dl13-ethyl-3-methoxy-16u-hydroxygona- 3,5-dien-17-one, formate mm 5.70, 5.80, 6.07 and 6.16;;

Analysis (percent): C, 73.22; H, 8.51. Calcd. for C H O (percent): C, 73.22; H, 8.19.

EXAMPLE 16 dl-13-ethyl-17a-ethynyl-16ot,17fi-clihydroxygon-4-en-3-one Equip a flask with magnetic stirrer, condenser, gas inlet tube then charge with dry tetrahydrofuran ml.) and 3 M ethereal methyl magnesium bromide (40 ml.). Bubble purified acetylene through the solution for 2.5 hours then add dl-l3-ethyl-3-methoxy-l6a-hydroxygona- 3,5-dien-17-one, formate (1.65 g.). Reflux the reaction gently under acetylene for 3 hours, cool and let stand overnight. Pour the reaction into 20% ammonium chloride solution, extract with ether-ethyl acetate then wash dry and evaporate the extract in vacuo. Dissolve the oil in ether-tetrahydrofuran, treat with activated charcoal, filter and evaporate in vacuo. Cover the oil With methanol (25 ml.) then add a solution of cone. hydrochloric acid (3 ml.), water (3 ml.) and methanol (3 ml.) and let the solution stand for 2 hours. Warm gently for 15 minutes on the steam bath, cool and add Water ml.). Extract with ethyl acetate and with ether. Wash, dry, and evaporate the combined extracts in vacuo. Treat the oil in methylene chloride with activated charcoal, filter and evaporate in vacuo. Crystallize the oil from ether to get 0.92 g.; M.P. -188. Retreat the solid in tetrahydrofuran with activated charcoal, filter and evaporate in vacuo. Dissolve the residue in hot methylene chloride, boil and replace the solvent with ether. Let stand, then filter to get 470 mg. of title product, M.P. 181-184".

AER. 3.05, 6.02 and 6.15 1. x533? 239 my (6 16,600)

I claim: 1. A compound of the structure Witt)? wherein R is alkyl of from 1 to 4 carbon atoms.

2. The compound according to claim 1, 16u,17,6-dihydroxy-13/3-ethyl-17a-ethynylgon-4-en-3-one.

3. The compound according to claim 1, 165,17fl-dihydroxy-13,8-ethyl-17a-ethynylgon-4-en-3-0ne.

9 10 4. A compound of the structure OH 0 References Cited UNITED STATES PATENTS 3,519,714 7/1970 Hughes et a1. 424238 v 10 HENRY A. FRENCH, Primary Examiner wherein R is alkyl of from 1 to 4 carbon atoms, R is US. Cl. X.R. alkyl of from 1 to 8 carbon atoms, and X is 0:0 or 999 

